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New page: left|200px<br /> <applet load="2pno" size="450" color="white" frame="true" align="right" spinBox="true" caption="2pno, resolution 3.30Å" /> '''Crystal structure o...
 
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[[Image:2pno.gif|left|200px]]<br />
<applet load="2pno" size="450" color="white" frame="true" align="right" spinBox="true"
caption="2pno, resolution 3.30&Aring;" />
'''Crystal structure of human leukotriene C4 synthase'''<br />


==Overview==
==Crystal structure of human leukotriene C4 synthase==
The cysteinyl leukotrienes, namely leukotriene (LT)C4 and its metabolites, LTD4 and LTE4, the components of slow-reacting substance of anaphylaxis, are lipid mediators of smooth muscle constriction and inflammation, particularly implicated in bronchial asthma. LTC4 synthase (LTC4S), the, pivotal enzyme for the biosynthesis of LTC4 (ref. 10), is an 18-kDa, integral nuclear membrane protein that belongs to a superfamily of, membrane-associated proteins in eicosanoid and glutathione metabolism that, includes 5-lipoxygenase-activating protein, microsomal glutathione, S-transferases (MGSTs), and microsomal prostaglandin E synthase 1 (ref., 13). LTC4S conjugates glutathione to LTA4, the endogenous substrate, derived from arachidonic acid through the 5-lipoxygenase pathway. In, contrast with MGST2 and MGST3 (refs 15, 16), LTC4S does not conjugate, glutathione to xenobiotics. Here we show the atomic structure of human, LTC4S in a complex with glutathione at 3.3 A resolution by X-ray, crystallography and provide insights into the high substrate specificity, for glutathione and LTA4 that distinguishes LTC4S from other MGSTs. The, LTC4S monomer has four transmembrane alpha-helices and forms a threefold, symmetric trimer as a unit with functional domains across each interface., Glutathione resides in a U-shaped conformation within an interface between, adjacent monomers, and this binding is stabilized by a loop structure at, the top of the interface. LTA4 would fit into the interface so that Arg, 104 of one monomer activates glutathione to provide the thiolate anion, that attacks C6 of LTA4 to form a thioether bond, and Arg 31 in the, neighbouring monomer donates a proton to form a hydroxyl group at C5, resulting in, 5(S)-hydroxy-6(R)-S-glutathionyl-7,9-trans-11,14-cis-eicosatetraenoic acid, (LTC4). These findings provide a structural basis for the development of, LTC4S inhibitors for a proinflammatory pathway mediated by three cysteinyl, leukotriene ligands whose stability and potency are different and by, multiple cysteinyl leukotriene receptors whose functions may be, non-redundant.
<StructureSection load='2pno' size='340' side='right'caption='[[2pno]], [[Resolution|resolution]] 3.30&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[2pno]] is a 12 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2PNO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2PNO FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.3&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GSH:GLUTATHIONE'>GSH</scene>, <scene name='pdbligand=LMT:DODECYL-BETA-D-MALTOSIDE'>LMT</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2pno FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2pno OCA], [https://pdbe.org/2pno PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2pno RCSB], [https://www.ebi.ac.uk/pdbsum/2pno PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2pno ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/LTC4S_HUMAN LTC4S_HUMAN] Defects in LTC4S are the cause of leukotriene C4 synthase deficiency (LTC4 synthase deficiency) [MIM:[https://omim.org/entry/246530 246530]. LTC4 synthase deficiency is a fatal neurometabolic developmental disorder. It is associated with muscular hypotonia, psychomotor retardation, failure to thrive, and microcephaly.
== Function ==
[https://www.uniprot.org/uniprot/LTC4S_HUMAN LTC4S_HUMAN] Catalyzes the conjugation of leukotriene A4 with reduced glutathione to form leukotriene C4.
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/pn/2pno_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2pno ConSurf].
<div style="clear:both"></div>


==Disease==
==See Also==
Known disease associated with this structure: Leukotriene C4 synthase deficiency OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=246530 246530]]
*[[Leukotriene C4 synthase|Leukotriene C4 synthase]]
 
__TOC__
==About this Structure==
</StructureSection>
2PNO is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with GTT and LMT as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Leukotriene-C(4)_synthase Leukotriene-C(4) synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=4.4.1.20 4.4.1.20] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2PNO OCA].
 
==Reference==
Crystal structure of a human membrane protein involved in cysteinyl leukotriene biosynthesis., Ago H, Kanaoka Y, Irikura D, Lam BK, Shimamura T, Austen KF, Miyano M, Nature. 2007 Aug 2;448(7153):609-12. Epub 2007 Jul 15. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17632548 17632548]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Leukotriene-C(4) synthase]]
[[Category: Large Structures]]
[[Category: Single protein]]
[[Category: Ago H]]
[[Category: Ago, H.]]
[[Category: Austen KF]]
[[Category: Austen, K.F.]]
[[Category: Irikura D]]
[[Category: Irikura, D.]]
[[Category: Kanaoka Y]]
[[Category: Kanaoka, Y.]]
[[Category: Lam BK]]
[[Category: Lam, B.K.]]
[[Category: Miyano M]]
[[Category: Miyano, M.]]
[[Category: Shimamura T]]
[[Category: Shimamura, T.]]
[[Category: GTT]]
[[Category: LMT]]
[[Category: helix bundle]]
[[Category: homo trimer]]
[[Category: lyase]]
[[Category: mapeg]]
[[Category: membrane protein]]
[[Category: mgst]]
 
''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 23:25:36 2007''

Latest revision as of 16:53, 13 March 2024

Crystal structure of human leukotriene C4 synthaseCrystal structure of human leukotriene C4 synthase

Structural highlights

2pno is a 12 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 3.3Å
Ligands:,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

LTC4S_HUMAN Defects in LTC4S are the cause of leukotriene C4 synthase deficiency (LTC4 synthase deficiency) [MIM:246530. LTC4 synthase deficiency is a fatal neurometabolic developmental disorder. It is associated with muscular hypotonia, psychomotor retardation, failure to thrive, and microcephaly.

Function

LTC4S_HUMAN Catalyzes the conjugation of leukotriene A4 with reduced glutathione to form leukotriene C4.

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

See Also

2pno, resolution 3.30Å

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